Frontiers in Psychiatry (Mar 2012)
Serotonin transporter genomic biomarker for quantitative assessment of ondansetron treatment response in alcoholics
Abstract
Paucity of sensitive biomarkers to quantify transient changes in alcohol consumption level remains a critical barrier for the development of efficacious therapeutic agents to treat alcoholism. Recently, in an 11-week, randomized, placebo-controlled, double-blind trial of 283 alcohol-dependent individuals, we demonstrated that ondansetron was efficacious at reducing the severity of drinking (measured as drinks per drinking day; DDD) in alcoholics carrying the LL compared with the LS/SS genotype of the serotonin transporter gene, 5′-HTTLPR. Using peripheral blood samples from a cohort of 41 of these subjects, we determined whether there was a relationship between mRNA expression level of the 5′-HTTLPR genotypes (measured at weeks 0, 4, and 11) and self-reported alcohol consumption following treatment with either ondansetron (4 μg/kg twice daily; N=19) or placebo (N=22). Using a mixed-effects linear regression model, we analyzed the effects of DDD and 5′-HTTLPR genotypes on mRNA expression levels within and between the ondansetron and placebo groups. We found a significant three-way interaction effect of DDD, 5′-HTTLPR genotypes, and treatment on mRNA expression levels (p=0.0396). Among ondansetron but not placebo recipients, there was a significant interaction between DDD and 5′-HTTLPR genotype (p=0.0385 and p=0.7938, respectively). In the ondansetron group, DDD was associated positively with mRNA levels at a greater rate of expression alteration per standard drink in those with the LL genotype (slope=+1.1698 in ln scale). We suggest that the combination of the LL genotype and 5′-HTTLPR mRNA expression levels might be a promising and novel biomarker to quantify drinking severity in alcoholics treated with ondansetron.
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